Cell Cycle Deficits in Neurodegenerative Disorders: Uncovering Molecular Mechanisms to Drive Innovative Therapeutic Development
Chitra Joseph1, Abubakar Siddiq Mangani1, Veer Gupta2, Nitin Chitranshi1, Ting Shen1, Yogita Dheer1, Devaraj KB1, Mehdi Mirzaei3, Yuyi You1,4, Stuart L. Graham1,4,*, Vivek Gupta1,*
1Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia 2School of Medicine, Deakin University, Melbourne, VIC, Australia. 3Department of Molecular Sciences, Macquarie University, North Ryde, NSW 2109, Australia 4Save Sight Institute, Sydney University, Sydney, NSW 2109, Australia
Cell cycle dysregulation has been implicated in the pathogenesis of neurodegenerative disorders. Specialised function obligates neuronal cells to subsist in a quiescent state of cell cycle once differentiated and therefore the circumstances and mechanisms underlying aberrant cell cycle activation in post-mitotic neurons in physiological and disease conditions remains an intriguing area of research. There is a strict requirement of concurrence to cell cycle regulation for neurons to ensure intracellular biochemical conformity as well as interrelationship with other cells within neural tissues. This review deliberates on various mechanisms underlying cell cycle regulation in neuronal cells and underscores potential implications of their non-compliance in neural pathology. Recent research suggests that successful duplication of genetic material without subsequent induction of mitosis induces inherent molecular flaws that eventually assert as apoptotic changes. The consequences of anomalous cell cycle activation and subsequent apoptosis are demonstrated by the increased presence of molecular stress response and apoptotic markers. This review delineates cell cycle events under normal physiological conditions and deficits amalgamated by alterations in protein levels and signalling pathways associated with cell-division are analysed. Cell cycle regulators essentially, cyclins, CDKs, cip/kip family of inhibitors, caspases, bax and p53 have been identified to be involved in impaired cell cycle regulation and associated with neural pathology. The pharmacological modulators of cell cycle that are shown to impart protection in various animal models of neurological deficits are summarised. Greater understanding of the molecular mechanisms that are indispensable to cell cycle regulation in neurons in health and disease conditions will facilitate targeted drug development for neuroprotection.
Figure 1. Schematic representation elucidating various factors involved in cell cycle activation and apoptosis induction in neurons. Growth factor deprivation (a), neurotoxic accumulation of protein polymers (b), DNA damage (c) and oxidative stress (d) may lead to aberrant cell cycle activation characterised by an increase in cyclin-dependent kinases (CDKs), cyclin, proliferating cell nuclear antigen (PCNA) and a decrease in CDK inhibitors. The synchronised effects of increased cdk4/6, cdk2 and decreased CDK inhibitors p21 and p16 (e) result in retinoblastoma protein (Rb) hyperphosphorylation and release of E2 Transcription Factor (E2F) that initiate transcription of target genes responsible for DNA replication. However, due to lack of mitotic signals (activation of cyclin A and cell division cycle 2 (cdc2)), these actively replicating cells are unable to exit the cell cycle and end up with double the amount of DNA. This leads to p53 induced apoptosis activation, and bax, caspase upregulation that drives the neurons to programmed cell death (PCD).
Cell cycle phase
CDK1/Cdc2, Cyclin B1
Neurons with neurofibrillary tangle s (IHC)
Whole brain lysate (WB)
Neuro fibrillary tangle bearing neurons (WB, IHC)
cyclin B1, cyclin D, CDK4, PCNA
Hippocampus, subiculum, locus coeruleus, dorsal raphe, inferotemporal cortex, cerebellum
Cyclin D1, cyclin E, Cyclin A pRb
Cortical neurons exposed to β amyloid
CDK2, CDK4, CDK6, cyclin B, and cyclin D
Peripheral lymphocytes (WB)
Frontal cortex, inferior parietal cortex and hippocampus (WB)
neurofibrillary tangles and senile plaque bearing neurons Hippocampus (WB, IHC)
Cyclin D, PCNA, Cyclin B1
Cdc2/Cyclin B1, CyclinD1, CDK4, pRb PCNA
Hippocampus (WB, IHC)
Senile plaques Hippocampus (IHC)
superior temporal gyrus (WB)
neurofibrillary tangles and senile plaque bearing neurons (IHC) Hippocampus
Glaucoma & other retinal disorders
Gadd45a and Ei24(p53 family)
Retina (qPCR and WB)
Optic nerve head (ONH) (Microarray)
CDKN2A & CDKN2B
RPE cells (WB)
RPE cells (WB)
Primary RPE cells (WB)
RPE cells (WB)
peripheral human retina (PR) and peripheral RPE-Choroid-Scleral (PRCS) tissues (RNA-Seq)
Macular cells (qRT PCR)
Retina (WB & IF)
Retinal pericytes (WB)
Amyotrophic lateral sclerosis
E2f, cyclin D1, CDK4, pRb
lumbar spinal cord and pre-/postcentral gyrus (IHC, WB)
Bax, caspase 3, caspase 8, p53, ppRb
lumbar spinal cord (IHC, IF, WB)
Spinal cord, motor cortex (IHC, WB)
Spinal cord (IHC, WB)
CDK4, CDK5, CDK6, cyclin D1
Spinal cord (IHC)
SN nuclei, Frontal cortex and hippocampus (IHC)
Dopaminergic neurons in SN (IHC, IF)
Dopaminergic neurons in SN(IF)
cyclin D, cyclin A, cyclin E and cyclin B
IF of embryonic rat mid brain neurons
Dopaminergic neurons in SN (IHC, WB, kinase assay) in MTP treated mice
caudate nucleus (WB) in human PD brain
Dopaminergic cells (IF, WB) in vitro (6-hydroxydopamine) and mouse model (PQ/MB) Whole brain lysates (WB) in human PD brains
Table 1 Cell cycle modulatory proteins/genes identified in Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and ophthalmic neurodegenerative disorders such as glaucoma, age related macular degeneration (AMD) and diabetic retinopathies are listed along with the tissues examined.
Figure 2. Schematic representation of cell cycle in healthy and degenerating neurons. In physiological conditions neural precursor cells go through G1, S, G2 and mitotic phases of cell cycle (inner circle) delivering early progenitor cell that can differentiate to mature neurons (left arrow). However, a mature dormant neuron in G0 phase may re-enter the cell cycle under pathological conditions. This cell then proceeds through all the different phases in interphase but is hindered at the end of G2 (outer circle). Instead of proceeding to mitotic (M) phase these tetraploid cells may undergo apoptosis (right arrow). Pharmacological compounds that affect various cell cycle stages and potentially could be neuroprotective at different stages of the cell cycle are also shown. Cyclin-dependent kinase (CDK5) and cyclin D in G1 phase can be inhibited by CDK5 inhibitory peptide (CIP), indirubin, and flavopiridol respectively. Roscovitine inhibits CDK5 interaction with multiple cyclins involved in G1 and S phase. Olomoucine imparts neuroprotection by regulating CDK5/cyclin interaction throughout interphase. Kenpaullone is a potent cdk1/cyclin B inhibitor effective in G2 phase.
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